Summary-Research Project 2 The high concentration of abandoned mine waste and rural nature of Tribal communities often brings community members into direct and frequent contact with low-level metal mixtures from un-remediated and abandoned mine sites, resulting in potentially toxic exposures occurring via inhalation, drinking water, and ingestion of food sources that are either directly or indirectly contaminated by wastes. The objective of research project 2 (RP2) is to assess the relationship of metal exposures (determined through biomonitoring of blood and urine samples) with immunologic outcomes in individuals from Tribal communities who live in proximity to legacy mine waste. This objective responds directly to concerns of the Tribal communities that chronic exposure to metal and metalloid mixtures affects immune responses and contributes to development of disease. Our overarching hypothesis is that there is an increased body burden of metals due to environmental exposure to mixed metal contaminants within the Tribal communities, and that this exposure results in immune dysregulation and autoimmune responses. We will 1) Determine whether exposure to metals or metal mixtures (measured through biomonitoring) increases the prevalence of anti-nuclear antibodies (ANA) and/or lymphocyte apoptosis in individuals from our three affected Tribal communities. 2) Determine whether exposure to metals or metals mixtures are associated with predictable changes in cytokine profiles or T and B cell phenotypes in individuals from our three Tribal populations and 3) Determine the effect of metal mixtures relevant to our three participating Tribal communities on exacerbation or induction of autoimmune disease and immune dysregulation via a drinking water exposure in in vivo animal models. A fundamental question addressed by these studies is whether certain combinations of environmental metal have independent, additive, or even synergistic toxic effects. Tribal communities are disproportionately exposed to a variety of heavy metals and metalloids, yet there are no population-based studies investigating the effect of mixed metals exposure on immune responses, especially across different Tribal communities with exposures to environmental metals. We have the unique opportunity to use the same research approaches on three different Native American Tribal populations to clearly identify commonalities and differences in exposures and exposure outcomes. A major goal and innovation of this study is the development of a common database with data from three Tribal communities (with planned expansion to other communities) on exposure and resulting immunologic parameters that have never been compiled. This data will be crucial to establishing commonalities and overlaps in exposures and health outcomes in these communities for which such significant health disparities exist.